PROJECT SUMMARY Pilot Research Project Epigenetic Factors and the Microbiome in Disparities in Colon Cancer Outcomes TUFCCC: Jean-Pierre Issa, MD and Carmen Sapienza, PhD (Co-Leaders) HC: Frida Kleiman, PhD (Co-Leader) Epidemiological data have demonstrated race and/or ethnicity differences in age-adjusted mortality for cancer, overall, and for the incidence and mortality rates of individual cancers. There are likely multiple reasons for such disparities, including socioeconomic factors (SES), such as education, access to healthcare, application of early detection methods and availability of advanced therapies. However, racial disparities in colorectal cancer provide one indication that biology-based factors are also likely to be at play. Not only are colorectal cancer mortality rates for African American men and African American women higher than for Caucasian men and women but African American patients appear less likely to develop microsatellite instable cancers (a type of cancer with improved outcomes) and tumors from African American patients appear to have a distinct mutation profile. Our hypothesis is that much of the racial disparity between African Americans and Caucasians in colon cancer incidence and outcomes are due to environmental and/or genetic differences between the two groups. This hypothesis is based on published data from our laboratories as well others, including the identification of DNA methylation differences in the normal colon mucosa of cancer patients that distinguish cancer patients from patients without cancer with high sensitivity and specificity. The methylation differences we identified occur in genes in which cancer-associated genetic and epigenetic changes have been identified but also include genes involved in the metabolism of lipids and carbohydrates, consistent with the notion that dietary factors influence risk for colon cancer. In addition, our more recent data identifies cancer- associated alterations to the gut microbiome, including increases in pathogenic species associated with inflammation. In this application, we will perform analyses that are exactly parallel to our previously published analyses and to our very strong preliminary data to test the hypothesis that the racial disparities in colon cancer are driven by race-associated environmental and genetic differences in the normal mucosa that interact with the gut microbiome to alter cancer risk. We will compare the DNA methylome of normal colon mucosa of cancer patients and patients without cancer in a race-stratified way to identify a cancer normal colon ?field-effect? signature that is race-associated and determine whether this signature is associated with chromatin changes that affect gene expression. We will also identify any microbiome components that are cancer-enriched and race associated. This study will serve as the exploratory groundwork for more mechanistic studies that will target the genetic and epigenetic pathways identified as race-associated in colon cancer.